Current insights on gut microbiome and chronic urticaria: progress in the pathogenesis and opportunities for novel therapeutic approaches

ABSTRACT Chronic urticaria (CU) is a prevalent skin disorder greatly impacting the patients’ life quality, in which immune dysregulation mediated by gut microbiome plays a significant role. Several studies have found the gut dysbiosis exists in patients with CU. In addition, infection may also be one of the causes of CU. The primary treatment currently used for CU is the second-generation non-sedating H1-antihistamines (nsAH). However, there are some limitations in current therapies. Based on the latest evidence, this review provides an updated overview of how the gut dysbiosis influences CU development, explores potential therapeutic approaches based on the gut microbiota and summarizes the interaction between gut microbiota and current treatment.


Introduction
Urticaria is an immune-related skin disorder that affects up to 20% of individuals over their lifetime.It can present as a pruritic rash, angioedema, or both. 1,2Urticaria, also known as hives, can be categorized into two main types: acute urticaria (AU) and chronic urticaria (CU).AU is mostly a self-limiting disease with a duration of less than 6 weeks, mostly related to infections, drugs or certain foods. 1 CU is characterized by spontaneous or inducible occurrence, lasting more than 6 weeks without a clear etiology, 1 including chronic spontaneous urticaria (CSU) and chronic inducible urticaria.It greatly impacts the quality of life of patients and imposes a substantial burden on them. 3he development of CU is considered to be closely related to the immune system. 4Relevant studies have shown that CU lesions have a large infiltration of immune cells, 5 such as mast cells, 6 eosinophils 7 and basophils. 8The activation of mast cells is a key factor in the development of CU, as it triggers the release of histamine, resulting in the characteristic symptoms of the disease. 6The researchers hypothesized that eosinophils in the blood are recruited to the skin during the active phase of CU, which is related to the interaction between eosinophils and mast cells through various mediators such as cytokines. 7During the active phase of CU, basophils in the blood are also recruited to the skin, influencing the pattern of IgE receptor-mediated mast cell degranulation. 8he interactions between mast cells and different immune cells are crucial in shaping the local microenvironment. 4he current primary treatment for CU is the second-generation non-sedating H1antihistamines (nsAH). 1 Evidence from randomized controlled trials strongly advocates for the use of these antihistamines. 1,9,10In cases where CU is inadequately controlled, adjunct therapies such as second-generation H1-antihistamines, leukotriene drugs, and short-term oral glucocorticoids may be considered. 2If the above treatments are ineffective, omalizumab may be considered.There is compelling evidence to advocate for the use of cyclosporine after ineffective treatment with omalizumab. 11However, current treatments have limited effectiveness in some patients with CU. 2 In recent years, several innovative targeted therapeutic options such as dupilumab 12,13 and Bruton's tyrosine kinase inhibitors, 12,13 are currently undergoing clinical trials for the treatment of CU.
Recent studies have shown that an imbalance in the gut microbiota is associated with the development of certain skin diseases. 14,15Clinical studies have demonstrated alterations in the gut microbiota of CU patients, indicating a potential role of the gut microbiota in the development of CU. [16][17][18][19][20][21] In this review, we provide a comprehensive overview of the currently available literature on gut dysbiosis in patients with CU and explore potential treatment strategies based on the gut microbiota.

Gut microbiome in chronic urticaria
It is universally acknowledged that CSU is mainly an immune-mediated inflammatory disease.Both Type I and Type II autoimmunity, specifically the presence of IgE antibodies to autoallergens and IgG autoantibodies to IgE or its high-affinity receptor (FcεRI), are thought to play a role in the development and progression of CSU. 22he activation, degranulation, and mediator release from cutaneous mast cells are crucial to the pathogenicity of CSU. 23The symptoms of CSU primarily result from the release of histamine, along with other mediators including prostaglandin D2 (PGD2), tumor necrosis factor (TNF) and various interleukin (IL), such as IL-4, IL-5, IL-13, IL-17, and IL-31, which can impact resident skin cells and other recruited target cells like T cells, eosinophils, and basophils.These recruited cells migrate from the blood into the skin in response to chemotactic factors, such as IL-5, complement 3a (C3a), complement 5a (C5a), TNF, IL-17 and so on, released by mast cells, activated endothelial cells, T helper (Th) 2 cells and other cells. 24Figure 1) A healthy gut is essential for overall health.In most scientific literature, the term "gut microbiota" or "gut flora" specifically refers to the bacteria that reside in the gastrointestinal tract of humans and other animals.Studies have indicated that the imbalance in the gut microbiota may contribute to skin diseases.Dysbiosis is linked to skin diseases like psoriasis, atopic dermatitis, and acne through inflammation and immune system disruption. 25CU, an immune-mediated skin disease, may also be influenced by gut flora. 4CSU is the primary focus of relevant studies among the different subtypes of CU.
Recent studies have examined the gut flora of patients with CSU, highlighting notable disparities in microbial composition between CSU patients and healthy controls (HCs).Inconsistencies in findings may stem from different CSU's subtypes and varied diagnostic techniques.The majority of research employed 16S rRNA sequencing to compare species and genera in HC and CSU groups.In some studies, quantitative polymerase chain reaction (PCR) or real-time PCR were used to identify species-specific variations (Table 1).Additionally, metabolomic analyses have also been instrumental in investigating metabolite alterations in CSU patients, offering insights into the disease's pathogenesis. 26,27lpha diversity of gut flora refers to the diversity of species in a single sample and can be measured using metrics such as Chao1 value, ACE value, and Shannon index. 28Beta diversity is a comparison of differences in diversity between samples. 19Studies have predominantly found lower alpha diversity in patients with CSU compared to HCs, along with a significant difference in the composition of gut flora between the two groups. 17,21,26,27,29xcept bacteria, the parasite is also an essential component of gut microbiome. 30,31Currently, parasite infection (PI) is described as an underlying cause of CSU. 32There are a variety of studies concerning the prevalence of PI in CSU and possible mechanisms.
Although virus and fungi also belong to gut microbiome, there are few researches directly focusing on the role of intestinal virus and fungi in the pathogenesis of chronic urticaria.4][35] As regard to the fungi, food yeasts and increased rates of sensitization to Candida albicans may be contributors to CU, but specific mechanisms have not been clarified. 36,37

Increased levels of opportunistic pathogens in CU patients
Enterobacteriaceae family is one of the proinflammatory members of the gut microbiota. 38bizadeh et al. conducted the initial study to explore changes in the gut microbiome of patients with CU using real-time PCR. 20The results revealed that the Enterobacteriaceae family was more prevalent in the fecal samples of CU patients, aligning with findings from other studies. 17,19,26,27Lu et al. also observed a higher abundance of Escherichia coli and Klebsiella spp. in the CSU group. 39A recent study analyzed the composition of gut microbiome in patients with CSU using multi-omics analysis, which revealed that CSU patients have lower gut flora diversity but higher levels of Klebsiella pneumoniae. 27Liu et al. observed a positive correlation between Clostridium disporicum and low quality of life. 17t the phylum level, the gut microbiota composition in CSU patients is comparable to that of HCs, comprising Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. 29In the study by Zhang et al. significant differences were observed between the CSU and HC groups, including Proteobacteria at the phylum level, Bacilli at the class level, Enterobacterales at the order level, Enterobacteriaceae at the family level, and Megamonas, Dialister, and Megasphaera at the genus level. 19The study particularly emphasized a pronounced increase in the phylum Proteobacteria within the CSU group, a finding supported by Wang et al. and Lu et al. 29,39 In addition to the aforementioned findings, Wang et al.'s study identified higher levels of the genera Lactobacillus, Turicibacter, and Lachnobacterium in the CSU group. 29Shi et al. explored the causal relationship between gut flora and CSU using Mendelian randomization analysis.The study identified phylum Verrucomicrobia, genus Defluviitaleaceae UCG011 and genus Coprococcus 3 as potential risk factors for urticaria. 40Helicobacter pylori (HP), known to colonize the stomach and duodenum, can lead to persistent infections.A meta-analysis showed that patients with CU had a higher prevalence of HP infection than controls (odd ratio = 1.66, 95%CI:1.12-2.45;p = 0.01) and that HP-negative patients were more likely to experience spontaneous remission of symptoms than positive patients. 41Another study showed that the eradication of bacteria doubled the probability of clinical remission of CU. 42 To explain these findings, researchers proposed one hypothesis suggesting that H. pylori's 21-35 kDa mixed protein components may stimulate the degranulation of human mast cells. 43In addition, some bacterial genes such as cagA, vacA and nap may encode specific proteins triggering an immune response that enhances pro-inflammatory pathways. 44

Decreased levels of beneficial bacteria in CU patients
Bacteroidetes is a predominant component of the intestinal flora.Genus Bacteroides is the primary producer of short-chain fatty acids (SCFAs), specifically acetic and propionic acids. 45Luo et al. discovered that the abundance of phylum Bacteroidetes was lower in CSU patients compared to the HCs, suggesting a possible protective role of Bacteroidetes against CSU. 46Research has shown that Bacteroides exerts a regulatory influence on human immunity, mainly by producing capsular polysaccharide A and SCFAs.Capsular polysaccharide A plays a role in maintaining and balancing immune system function, as well as in preventing bacterial and viral infections. 45Both acetate and propionate serve as potent anti-inflammatory agents, capable of suppressing the release of proinflammatory cytokines by neutrophils and macrophages. 47t is worth noting that Firmicutes and Bacteroidetes constituted 90% of the beneficial bacterial strains in the intestine. 48Phylum Firmicutes can break down insoluble dietary fiber to release nutrients and promote the proliferation of different bacterial species in the gut. 49Liu et al. and Wang et al. reported a decrease in the number of phylum Firmicutes in the CSU group. 17,26However, this conclusion has not yet reached a consensus. 19,29,46oreover, Wang et al. found that genus Phascolarctobacterium was higher in the healthy group. 29And patients with chronic spontaneous urticaria and symptomatic dermographism (CSD) have significantly lower levels of Subdoligranulum and Ruminococcus bromii, which may have diagnostic values. 17ezazadeh et al. discovered that the relative amounts of Lactobacillus and Bifidobacterium were significantly higher in fecal samples from controls compared to patients with CU, indicating a protective effect against CU. 35This may be attributed to their ability to induce regulatory T (Treg) cells. 36Ćesić et al. found reduced levels of Lachnospiraceae members responsible for SCFA production in the gut flora of patients with CSU. 50In the Mendelian Randomization analysis, order Burkholderiales and genus Eubacterium xylanophilum group were found to be potentially protective against urticaria. 40

Influence of gut microbiome in chronic urticaria
As mentioned above, visible changes happened in the gut microbiome of CSU patients.Mast cells are more likely to be activated in patients with CSU compared to the HCs, which may be related to a lower threshold for activation signals or reduced exposure to inhibitory signals. 51,52ipopolysaccharide (LPS) and pro-inflammatory cytokines can make mast cells more susceptible to activation, whereas SCFAs can inhibit mast cells activation. 53These factors affecting mast cells' activation can be produced by the gut flora.(Figure 2).

The disrupted immune regulatory function of SCFAs
SCFAs mitigate inflammation by enhancing prostacyclin E2 and IL-10 production via epigenetic mechanisms, while also promoting the differentiation of Treg cells and curbing the activity of Th17 cells, thus playing a key role in immune regulation. 47,54Zhu et al. found that SCFAs can attenuate mast cell-driven skin inflammation through animal experiments. 27iu et al. used 16s rDNA sequencing and quantitative PCR to identify the flora of patients with CSD.Their comprehensive analysis yielded a reduction in beneficial bacteria producing SCFAs, like Subdoligranulum and Ruminococcus bromii. 17Abnormal cytokine expression and the dysfunction of Treg cells are prevalent in patients with CU. 20 Th2 cells release cytokines like IL-4, IL-5, and IL-13, which stimulate the production of IgE and can activate mast cells, basophils, and eosinophils.Furthermore, IL-4 enhances the expression of the IgE receptor. 55Based on previous evidence, the researchers proposed a hypothesis that the reduction of SCFAs would further suppress the production and function of Treg cells, which leads to an imbalance of the Th1/Th2 ratio and an increase in the production of IL-4 and IgE. 17

Rezazadeh et al. found that Lactobacillus and
Bifidobacterium may also play a protective role against CU by inhibiting inflammation through the differentiation of Treg cells. 56ncreased Th17 cells have been detected in patients with CU compared to HCs. 57 Luo et al. found that the genus Prevotella was more abundant in the CSU group than in HCs and was shown to stimulate Th17 immune response and recruit neutrophils to trigger persistent inflammation in mouse experiments. 46Zhang et al. observed a notable rise in the relative abundance of the Proteobacteria phylum in CSU patients. 19This increase in Proteobacteria is commonly seen in individuals with asthma and allergic conditions, potentially because Proteobacteria can induce allergic responses by upregulating the expression of Th17-related genes. 58CFAs not only contribute to maintain the immune microenvironment but also stabilize the intestinal mucosal epithelial barrier. 59Enhancing the diversity of the gut microbiota by lowering pH, maintaining the barrier integrity of the epithelium, and regulating the secretion of mucus may serve as other protective mechanisms. 60,61Yüksekal et al. found that the mean fecal pH of CSU patients (7.17) was higher than that of HCs (6.7), which was associated with reduced production of SCFAs. 18Lower intestinal pH supports the growth of beneficial bacteria like Bifidobacterium and Lactobacillus, which in turn helps maintain a healthy pH balance and prevents the colonization of harmful bacteria. 62

The intensified pro-inflammatory role of LPS
Gram-negative bacteria are the primary constituents of the intestinal flora, and lipopolysaccharides on their cell walls can stimulate IgE-induced MC degranulation and the release of inflammatory mediators through Toll-like receptor 4. 63 An increase in opportunistic pathogens was discovered in the intestines of CSU patients, while decreased levels of SCFAs led to heightened intestinal mucosal permeability, ultimately resulting in elevated levels of circulating LPS. 27n increased abundance of the Enterobacteriaceae family, the main opportunistic pathogens producing LPS, was found in the feces of patients with CU, which promotes Th2 cell differentiation and produces IL-4. 20,21The discovery was further validated by research conducted by Lu et al., which identified elevated Escherichia colilevels within CSU patients. 39Zhu et al. also indicated that a high level of Klebsiella pneumoniae increased passive cutaneous anaphylactic shock response in recipient mice and raised blood levels of LPS. 27

The role of parasite infection in CU
Parasitic infections have also been identified as contributors to abnormal intestinal microecology associated with the pathogenesis of CSU.The association between internal parasite infection and CSU has been studied in several researches, summarized by a systematic review. 64Patients with CSU were more frequently diagnosed with protozoa and exhibited a significantly elevated risk of toxocariasis seropositivity and sensitization to Anisakis simplex compared to the HCs.They also showed higher prevalence of fasciolosis, Anisakis simplex sensitization, and Blastocystis hominis allele 34 (ST3) compared to controls.Additionally, Blastocystis hominis was the most common parasite in children with CSU.After antiparasitic medication, all incorporated children came back to normal. 65y analyzing crude extracts and isolated components from whole larvae of Ascarididae (Anisakis simplex and Toxocara canis), Viñas et al. observed that Anisakis appears to play a more significant role than Toxocara in the association between urticaria and parasitic infestations, with tropomyosin and Ani s l serving as crucial markers. 66ematodes, a type of helminth, affect millions of individuals worldwide.Various nematode infections have been linked to the development of urticaria and/ or angioedema, such as Dirofilaria spp, Enterobius vermicularis, Gnathostoma spp and so on. 67elminth infections may impact the onset and progression of CSU via various pathways involving the activation of mast cells and basophils. 24arasite-specific IgE activates mast cells and basophils via high-affinity IgE receptors (FceRI).Helminths, such as Toxocara canis or Fasciola hepatica, and protozoa, such as Blastocystis hominis or Giardia lamblia, have the ability to induce the production of high levels of specific IgE antibodies against their antigens in the host, which can result in sensitization and degranulation of host mast cells. 68,69dditionally, helminth parasites disrupt the body's protective barriers, prompting a Th2 immune response and tissue repair. 64And the parasites themselves inhibit the differentiation of Th1 cells and encourage the development of Th2 cells, while B cells aid Th1 responses by producing IgG1-3, forming immune complexes (CIC) with parasite antigens.This process activates the complement system and generates anaphylatoxins C5a and C3a to act on mast cells, contributing to the development of urticaria. 70,71

Other possible metabolite-related mechanisms
In metabolomics analyses, SCFAs were the predominant metabolites, while unsaturated fatty acids may also be essential in the pathogenesis of CSU.Unsaturated fatty acids such as arachidonic acid and docosahexaenoic acid have been shown to stimulate the growth of Bacteroides and have antiinflammatory effects, 72 supported by Wang et al. and Luo et al. 26,46 Lachnospira showed a negative correlation with arachidonic acid, while Gemmiger exhibited a negative correlation with (±) 8-HETE, a product of the enzymatic oxidation of arachidonic acid. 46,73Furthermore, purine metabolites such as adenine and adenosine were also increased in the CSU group.A mouse experiment found that inflammatory cells in allergic mice may result in increased levels of adenine and adenosine, providing further evidence that inflammation contributes to the pathogenesis of CSU. 74

The interaction between gut microbiome and current treatment
Currently, standardized protocols have been utilized to treat CSU.However, the effectiveness of these treatments for CSU patients can be affected by several factors, including gut flora.Some patients exhibit nsAH resistance, characterized by an inadequate response to any dose of nsAH, posing a significant challenge in CSU management.Patients with nsAH resistance have a more intense intestinal or systemic inflammatory response.1 In another study by Liu et al. genus Lachnospira was identified as a biomarker for nsAH characteristics. 76However, further research is needed to investigate the exact mechanisms.
One meta-analysis revealed that HP may be linked to the development and persistence of CSU. 42The efficacy of HP eradication therapy in alleviating CSU symptoms was found to be significant.Interestingly, CSU patients who received antibiotic treatment for HP eradication exhibited a notably higher rate of CSU remission, regardless of HP eradication status.As regard to parasite, majorities of CSU patients with PI were deemed suitable for the antiparasitic therapy. 64urthermore, the current treatment has also been demonstrated to contribute to the alteration of gut microbiome in CSU patients.Following omalizumab therapy, a notable decrease was observed in the relative abundance of Alphaproteobacteria and Betaproteobacteria at the class level, as well as Burkholderia, Rhodococcus, and Sphingomonas at the genus level. 77This reduction may be a contributing factor to the favorable recovery outcomes.

Approaches targeting gut microbiome for CU therapy
CU poses a common and clinically challenging disorder, with approved therapies effectively managing symptoms but lacking efficacy in altering the natural disease progression. 78Therefore, there exists a need for enhanced therapy methodologies, and the correlation between gut microbiota and CU presents a propitious therapeutic pathway.Treating CU by regulating intestinal microecology is currently a prominent research focus.(Figure 3).

Probiotics
0][81] Several mechanisms can be postulated to elucidate the protective properties of probiotics against chronic urticaria.Firstly, evidence suggests a reduction in both quantity 82 and functionality 83 of Treg cells in patients with CU.5][86][87] By stimulating the synthesis of anti-inflammatory mediators, this induction reduces inflammation and promotes an anti-inflammatory environment that serves as a protective mechanism against CU. 20Moreover, through the secretion of antimicrobial substances, suppression of bacterial toxin production, and competition with pathogens for epithelial adhesion and nutrients, probiotics maintain a well-balanced intestinal bacterial ecology and improve intestinal barrier function, which in turn reduces the production of deleterious metabolites in the body. 88Thus, dysregulation may become systemic as a result of alterations in the gut microbiota of patients with CU.This highlights the rationale for contemplating altering of the gut microbiome through the administration of probiotics.
0][91][92][93][94][95] Also, significant evidence implies that the gut microbiota may exert a significant influence on CU.Nonetheless, there remains a scarcity of dedicated case series or trials addressing this specific aspect.
As mentioned above, evidence from Nabizadeh's and Rezazadeh's studies suggests that some gut microbiota, indicating a safeguarding influence against CU, have the potential to participate as probiotics in the treatment and mitigation of CU.
Nettis et al. conducted a study to investigate the impact of a combination of two probiotics (Lactobacillus salivarius LS01 and Bifidobacterium breve BR03) on clinical progression in patients with refractory CSU.Assessment of patient improvement following probiotic administration was conducted using the 5-question urticaria quality of life questionnaire and the urticaria activity score over 7 days (UAS7) at baseline and week 8.During the probiotic intervention period, among 38 patients, 9 (23.7%)exhibited mild improvement in clinical symptoms; 1 (2.6%) demonstrated significant improvement; and 1 (2.6%) achieved complete resolution of urticaria symptoms.Symptoms remained unchanged in 27 patients (71.1%).Their findings substantiate the therapeutic efficacy of this probiotic combination in reducing symptomatology scores for certain CSU patients, primarily those with allergic rhinitis symptoms persisting despite treatment with H1 antihistamines, thereby enhancing their overall quality of life without any side effects. 96esloratadine dry suspension was administered to both groups of children in a randomized placebo-controlled study by Bi et al., which involved 206 children with CU.In the treatment group, 104 children were additionally administered Yimingjia® (a lyophilized mixture of six organisms at a concentration of 5 × 10 9 CFU live total bacteria per gram.After 4 weeks of monitoring, the treatment group exhibited a remarkable reduction in both wheal size and attack frequency, with 80.8% achieving a significant overall response rate (comprising significant improvement and complete response) compared to the 62.5% observed in the placebo group. 97This work further confirms the possible effectiveness of particular probiotic strain combinations in addition to provide evidencebased support for the use of probiotics in the treatment of CU.

Prebiotics
Prebiotics refer to supplements or foods containing non-digestible components that not only selectively promote the growth and/or activity of beneficial indigenous probiotic bacteria but also enforce the immune system. 98n a prospective, double-blind, placebocontrolled study by the Arslanoglu team, healthy full-term infants at atopic risk were fed hypoallergenic formula with prebiotics (0.8 g/100 ml galactooligosaccharides (scGOS)/fructooligosaccharides (lcFOS)) in 42 and placebo (0.8 g/100 ml maltodextrin) in 50 during the first 6 months of life and subsequently completed a 5-year follow-up.The incidence of allergic urticaria was lower in children in the scGOS/lcFOS group (6%) compared to the placebo group (38%).The protective effect of oligosaccharide prebiotics (scGOS/lcFOS) against allergic urticaria in high-risk infants starting early in life and continuing from infancy to 5 years of age was demonstrated. 99In another prospective, randomized, double-blind, placebo-controlled trial conducted by van der's team, healthy full-term infants of parents with a history of atopic dermatitis were fed hypoallergenic formula and divided into two groups, with prebiotics added to the intervention group (8 g/liter of scGOS/lcFOS), and placebo added to the placebo group (8 g/liter of maltodextrin).At the end of the 6-month intervention period, blinded follow-up continued until the infant was 2 years old.The cumulative incidence of allergic urticaria was higher in the placebo group (10.3%) than in the intervention group (1.5%). 94In conclusion, studies related to the application of prebiotics singly for the prevention of urticaria, mainly conducted in infants with scGOS/lcFOS, have demonstrated an effective protective effect.In addition, long-term follow-up studies with a larger population and a wider age range and using a wider variety of prebiotics are necessary to assess the potential preventive effect of such prebiotics on urticaria.

Synbiotics
Combining probiotics and prebiotics that work together synergistically, synbiotics possess properties of both probiotics and prebiotics and are developed to address potential challenges in probiotic survival within the gastrointestinal tract, thereby benefiting the host's health. 89,100tefi' s team carried out a blinded randomized controlled clinical trial on 42 patients with CU for 8 weeks.Patients were assigned to control (only antihistamine) and intervention groups (antihistamine + synbiotic) through computerized randomization with a 1:1 allocation ratio.Intervention groups received twice-daily oral probiotic capsules named LactoCare, which contains high amounts of beneficial bacteria including Lactobacillus rhamnosus, Lactobacillus casei, Lactobacillus acidophilus, Bifidobacterium breve, Lactobacillus bulgaricus, Bifidobacterium longum, Streptococcus thermophilus and fructooligosaccharides as prebiotic.There was 66% score reduction in the intervention group compared to 53% reduction in the control group.In the control and intervention group improvement of dermatology life quality index was 44% and 66%, respectively.While there wasn't a significant difference in effectiveness between using probiotics and antihistamines together versus using antihistamines alone based on UAS7 scores, patients receiving the combination therapy may experience a higher reduction in itching, number of hives, and total UAS7 score. 101he aforementioned studies reaffirm the efficacy, safety, and satisfaction of probiotics, prebiotics, and synthetic options as adjunctive therapies for managing CSU.These interventions offer effective relief from symptoms and enhance quality of life, exhibiting no apparent adverse effects.Nevertheless, loss to follow-up and short followup times are among the major limitations of these studies.Moreover, given the small number of relevant clinical trials and the small sample size included, more randomized controlled trials with blinding of patients are needed.Moreover, comprehensive, and intuitive mechanistic studies regarding the efficacy of probiotics and prebiotics in CU are currently lacking.In addition, the high cost of symbiotic organisms may be a limiting factor for further research on such topics.

Fecal microbiota transplantation
Remarkably effective in altering the gut microbiota, fecal microbiota transplantation (FMT) presents a viable therapeutic approach.The clinical reactions observed in a range of disorders following FMT demonstrate the intricate link between microbiota and host.These problems include, but are not limited to, Clostridium difficile infection, inflammatory bowel disease, diabetes mellitus, cancer, liver cirrhosis, and gut-brain disorders. 102ccording to earlier research, FMT has potential for use in dermatological applications.FMT suppresses many representative inflammatory cytokines and has demonstrated a quicker tendency in reversing the skin's epidermal layer's increased thickness. 103Another study by Kim's group used mice as experiment subjects and showed that FMT may raise levels of essential SCFAs in gut physiology and restore intestinal microbiota to a donor-like condition.Moreover, FMT decreases IgE levels, balances Th1/Th2 responses, controls gut microbiotamediated Treg cells, and diminishes mast cells, eosinophils, and basophils, all of which help to lessen allergic reactions in atopic dermatitis. 104u et al. reported a case in which a female patient who had experienced recurring paroxysmal stomach discomfort with urticaria for six years underwent four sessions of colonic FMT administered by transendoscopic enteral tube.At the oneyear follow-up, there was a noticeable improvement in the patient's symptoms, which allowed the treatment to end and the patient to eventually resume their regular social and eating activities.Furthermore, post-FMT gut microbiota composition underwent considerable alterations, as revealed by 16S rRNA sequencing analysis of fecal samples.These changes included an increase in Prevotella abundance and a decrease in Bacteroides and Faecalibacterium abundance.Additionally, gate-level analysis showed a lower steroidogenic/bacteroidogenic ratio, indicating a change in the gut microbiota of individuals with cystic urealitis and perhaps supporting the maintenance of gut microbiota homeostasis. 105n conclusion, the utilization of the microbiota represents the primary paradigm shift in the application of microbial cells.We need more clinical investigations of FMT for CU because the available clinical evidence is currently limited.For the benefit of more CU sufferers, thought needs to be made to standardizing FMT into a practical and dependable therapy option in the meantime.

Other therapeutic strategies
The scientific literature highlights diet as a pivotal factor in molding the gut microbiota, host metabolites, and barrier immune system, contributing to approximately 20% of the variation observed in the human gut microbiome. 106,107Changes in diet quickly impact the diversity of the gut microbiota, favoring the proliferation of specific bacterial populations while influencing gut pH, intestinal permeability, and the production of bacterial metabolites, potentially triggering inflammation. 108owever, stressing that food quality and nutrientsrather than quantity -are thought to be the main determinants of a good or unhealthy diet is important. 109Currently, studies have shown that certain foods can alter the composition of gut microbiota and alleviate symptoms of dermatologic symptoms, like olive-derived antioxidant dietary fiber. 110here are studies suggesting that the Mediterranean diet may influence the gut microbiota, which in turn affects the CU.The Mediterranean diet, characterized by its healthful eating habits, has been linked to decreased chances of developing cardiovascular diseases and metabolic syndrome. 111This eating regimen is marked by a blend of intricate carbohydrates rich in fiber, polyunsaturated fatty acids known for their antiatherogenic and anti-inflammatory effects, and bioactive compounds boasting antioxidant properties like flavonoids, phytosterols, terpenes, and polyphenols, serving as an exemplar of nutritious eating. 112A study revealed that the mean Mediterranean diet score was 5.40 ± 1.88 in the group of patients with CSU, compared to 6.30 ± 1.39 in the HCs (p < 0.001).The urticaria activity score in CSU patients over 7 days was inversely associated with the Mediterranean diet score, while the urticaria control test score was positively correlated. 113The study suggests that the Mediterranean diet's anti-inflammatory and antioxidant properties may help alleviate systemic inflammation and oxidative stress, 114 which contribute to the pathogenesis of CSU disease.In addition, adherence to the Mediterranean diet is linked to the restoration of balanced gut microbiota, with increases observed in Bacteroidetes and specific beneficial Clostridium groups, while decreases are noted in Proteobacteria and Bacillaceae phyla. 115estern diets drive an imbalanced gut microbiota, marked by an increased Firmicutes: Bacteroidetes ratio.Conversely, the Mediterranean diet fosters the growth of beneficial bacteria and their metabolites, while mitigating dysbiosis and reducing levels of LPS. 116MD pattern was also characterized by greater diversity, better intestinal barrier function and permeability. 117espite the fact that it may play a crucial part in the composition and activity of the gut microbiota and the ensuing immunological and inflammatory responses, there is surprisingly little data about how dietary diversity affects the microbiome of patients with convalescent units.To better understand the role of dietary, environmental, and lifestyle factors that may lead to immunological dysfunction, CU etiology must be thoroughly explored.There is a need to bring together the dietary diversity and dermatologic expertise of dietitians, nutritionists, immunologists, microbiologists, dermatopathologists, and biotechnologists in well-defined methodologies for well-conducted randomized controlled trials.
In addition, some adjuvant therapies further influence the course of the disease by affecting the species and quantity of gut bacteria, thus providing insights into CU symptom remission.Helminth therapy, as an allergy immunotherapy, has been found to be therapeutic for a selection of immune and inflammatory diseases like rheumatoid arthritis 118 and multiple sclerosis. 119Strong evidence from animal studies demonstrates that worms not only reduce parasite-specific immune responses but also modulate their own immunity and allergic inflammatory responses, improving metabolic balance. 120Active infection with Ascaris lumbricoides appears to confer protection against atopic dermatitis in Cuban children, whereas previous infection with Enterobius vermicularis. 121he word "helminth" comes from the Greek word "helmins," meaning "worm."Species categorized as annelids (segmented worms), nematodes (roundworms), trematodes (flukes), and cestodes (tapeworms) are the four primary families of human helminths. 122The two ways in which helminth therapy works are (1) directly through immune system influence, and (2) by alteration of the gut microbiota, 123 which has an effect on the organism.Helminths evade immunological recognition and confrontation by manipulating the animals' natural immune responses.Pre-existing allergy or immunological-related conditions in the host may go into remission or potentially go away completely as a result of this immune adjustment. 124In another research, Paneth cells and Goblet cells produce small proline-rich protein 2A after helminth infection, which is triggered by type 2 immunity. 125owever, further evidence in larger studies is needed to prove or disprove their safety and efficacy.Probiotics, prebiotics, synbiotics, nutrition, and FMT that target the gut microbiota have been demonstrated in many organic disease models and/ or clinical studies to have preventative potential.More focus and acceptance should be placed on methods for using microbiota in clinical and scientific research.Even while research on other treatment approaches, such as helminth therapy, which targets the gut microbiota, is continuing and shows promise, its processes are yet unknown.Clinical trials often have limited sample sizes, which makes it difficult to evaluate safety and efficacy impartially.Moreover, barriers to the clinical use of linked drugs and production costs continue to exist.These analog medications are difficult to make, which indicates that they won't be easily accessible for clinical usage very soon.

Conclusion
The composition and alterations of the gut microbiome have a significant impact on the pathological state of CU, and analysis of these host-bacteria interactions could enhance our comprehension of the mechanisms through which they impact and influence the progression of CU.By identifying these mechanisms and targeting the intestinal microbiome, researchers hope to develop new therapeutic strategies such as probiotics, prebiotics, synbiotics and FMT.We believe that these gut bacteria-based therapeutic strategies have great future potential for application in the treatment and prevention of CU.Researches on the exact mechanism of the gut microbiota in CU is still insufficient and it is hoped that researchers will in the future clarify the exact mechanism of the gut microbiota in the pathogenesis of CU as a basis for high quality clinical research, especially applied research.

Figure 1 .
Figure 1.The manifestations and pathophysiology of chronic urticaria.Both IgE-mediated type I and IgG-mediated type II allergies are the main pathophysiological mechanisms of CU, through which the MCs are activated and then release various inflammatory factors.Eosinophils, T cells and basophils can be recruited from the blood to the skin in response to these factors.Lower PH, higher permeability, elevated level of inflammation and the barrier disruption can be discovered in the intestine of CU patients, whose skins show wheals and angioedema.CU, chronic urticaria; MCs, mast cells; PDG2, prostaglandin D2; TNF-ɑ, tumor necrosis factor-ɑ; IL, interleukin; FcεRI, high-affinity IgE receptor (By Figdraw).

Figure 2 .
Figure 2. The alteration and influence of gut microbiome in chronic urticaria.(a) Gut dysbiosis: decreased levels of SCFAs-producing pathogens, increased levels of opportunistic pathogens and relevant intestinal infections, including HP and parasite.(b) Changes of metabolites: the levels of SCFAs and unsaturated fatty acids are reduced in the intestine of CU patients, while those of LPS and purine metabolites are elevated.(c) Intensified inflammation in intestine: The upregulation of LPS and downregulation of SCFAs appear as a result of gut dysbiosis, contributing to the abnormal differentiation of naïve T cells.The levels of IL-4 and IL-17 are elevated due to more Th2 and Th17, and less Treg and Th1.MCs are activated to release some inflammatory mediators like IL-3, TNF-ɑ and histamine.(d) Roles of parasite infection: enhancing the sensitivity of MCs; breaking the mucosal barrier and amplify the intestinal permeability;producing metabolites and interact with DCs to influence the differentiation of naïve T cell; forming CIC (IgG and parasite antigen) and activate the complement system to promote the release of inflammatory mediators.SCFAs, short chain fatty acids; HP, helicobacter pylori; CU, chronic urticaria; LPS, lipopolysaccharides; IL, interleukin; TNF-ɑ, tumor necrosis factor-ɑ; Th, T helper cells; Treg, regulatory T cells; MCs, mast cells; C3a, complement 3a; C5a, complement 5a; DCs, dendrite cells; CIC, immune complexes (By Figdraw).

Table 1 .
A summary of current evidence on the association between gut microbiome composition and chronic urticaria (mainly CSU).
Song et al. conducted a study comparing the intestinal flora of CSU patients with and without nsAH resistance.The study found that CSU patients with nsAH resistance had higher levels of genus Prevotella, Megamonas,